Paternal microbiome perturbations impact offspring fitness.

The gut microbiota operates at the interface of host-environment interactions to influence human homoeostasis and metabolic networks1-4. Environmental factors that unbalance gut microbial ecosystems can therefore shape physiological and disease-associated responses across somatic tissues5-9. However, the systemic impact of the gut microbiome on the germline-and consequently on the F1 offspring it gives rise to-is unexplored10. Here we show that the gut microbiota act as a key interface between paternal preconception environment and intergenerational health in mice. Perturbations to the gut microbiota of prospective fathers increase the probability of their offspring presenting with low birth weight, severe growth restriction and premature mortality. Transmission of disease risk occurs via the germline and is provoked by pervasive gut microbiome perturbations, including non-absorbable antibiotics or osmotic laxatives, but is rescued by restoring the paternal microbiota before conception. This effect is linked with a dynamic response to induced dysbiosis in the male reproductive system, including impaired leptin signalling, altered testicular metabolite profiles and remapped small RNA payloads in sperm. As a result, dysbiotic fathers trigger an elevated risk of in utero placental insufficiency, revealing a placental origin of mammalian intergenerational effects. Our study defines a regulatory 'gut-germline axis' in males, which is sensitive to environmental exposures and programmes offspring fitness through impacting placenta function.

Myelomeningocele sac associated with worse lower-extremity neurological sequelae: evidence for prenatal neural stretch injury?

OBJECTIVE: To determine whether the presence of a myelomeningocele (MMC) sac and sac size correlate with compromised lower-extremity function in fetuses with open spinal dysraphism. METHODS: A radiology database search was performed to identify cases of MMC and myeloschisis (MS) diagnosed prenatally in a single center from 2013 to 2017. All cases were evaluated between 18 and 25 weeks. Ultrasound reports were reviewed for talipes and impaired lower-extremity motion. In MMC cases, sac volume was calculated from ultrasound measurements. Magnetic resonance imaging reports were reviewed for hindbrain herniation. The association of presence of a MMC sac and sac size with talipes and impaired lower-extremity motion was assessed. Post-hoc analysis of data from the multicenter Management of Myelomeningocele Study (MOMS) randomized controlled trial was performed to confirm the study findings. RESULTS: In total, 283 MMC and 121 MS cases were identified. MMC was associated with a lower incidence of hindbrain herniation than was MS (80.9% vs 100%; P < 0.001). Compared with MS cases, MMC cases with hindbrain herniation had a higher rate of talipes (28.4% vs 16.5%, P = 0.02) and of talipes or lower-extremity impairment (34.9% vs 19.0%, P = 0.002). Although there was a higher rate of impaired lower-extremity motion alone in MMC cases with hindbrain herniation than in MS cases, the difference was not statistically significant (6.6% vs 2.5%; P = 0.13). Among MMC cases with hindbrain herniation, mean sac volume was higher in those associated with talipes compared with those without talipes (4.7 ± 4.2 vs 3.0 ± 2.6 mL; P = 0.002). Review of the MOMS data demonstrated similar findings; cases with a sac on baseline imaging had a higher incidence of talipes than did those without a sac (28.2% vs 7.5%; P = 0.007). CONCLUSIONS: In fetuses with open spinal dysraphism, the presence of a MMC sac was associated with fetal talipes, and this effect was correlated with sac size. The presence of a larger sac in fetuses with open spinal dysraphism may result in additional injury through mechanical stretching of the nerves, suggesting another acquired mechanism of injury to the exposed spinal tissue. Copyright © 2019 ISUOG. Published by John Wiley & Sons Ltd.

Intrauterine big toenail imprints: A new cause of congenital skin dimples.

Congenital skin dimples (SD) are small cutaneous depressions that can be noted on any part of the body and may be caused by traumatic, mechanical, metabolic, and genetic factors as well as by exposure to infections or drugs. We describe 3 cases of unrelated healthy newborns displaying SD and discuss as a possible explanation the persistent friction of the big toenail onto the immature skin of the fetus during intrauterine life causing as depression in the skin.

Fetal brain imaging following laser surgery in twin-to-twin surgery.

OBJECTIVE: To describe the incidence and nature of prenatal brain damage following fetoscopic laser selective coagulation (FLSC) of placental vessels for twin-to-twin transfusion syndrome (TTTS). DESIGN: Retrospective observational study. SETTING: Single center cohort. POPULATION: All consecutive cases referred for TTTS treated by FLSC between 2003 and 2015. METHODS: After the FLSC, patients were followed weekly by ultrasound. Fetal magnetic resonance imaging (MRI) scans were systematically planned at 30-32 weeks of gestation. MAIN OUTCOME MEASURES: Brain damage diagnosed prenatally by ultrasound or MRI. RESULTS: In total, 1023 cases were reviewed. Brain damage was diagnosed prenatally in 22/1023 (2.1%) cases. Diagnosis was performed by ultrasound prior to MRI in 18 (82%) cases. All lesions were within the spectrum of ischaemic haemorrhagic lesions. Postoperative twin anaemia polycythaemia sequence and recurrence of TTTS were significantly associated with brain damage. CONCLUSION: The incidence of prenatal brain damage is low following FSLC, and is strongly associated with incomplete surgery. TWEETABLE ABSTRACT: Following FSLC for TTTS, prenatal brain damage occurs in 2% of cases and is associated with incomplete surgery.

Role for Cystathionine γ Lyase (CSE) in an Ethanol (E)-Induced Lesion in Fetal Brain GSH Homeostasis.

Earlier, we reported that gestational ethanol (E) can dysregulate neuron glutathione (GSH) homeostasis partially via impairing the EAAC1-mediated inward transport of Cysteine (Cys) and this can affect fetal brain development. In this study, we investigated if there is a role for the transulfuration pathway (TSP), a critical bio-synthetic point to supply Cys in E-induced dysregulation of GSH homeostasis. These studies utilized an in utero E binge model where the pregnant Sprague⁻Dawley (SD) rat dams received five doses of E at 3.5 g/kg by gastric intubation beginning embryonic day (ED) 17 until ED19 separated by 12 h. The postnatal day 7 (PN7) alcohol model employed an oral dosing of 4 g/kg body weight split into 2 feedings at 2 h interval and an iso-caloric and iso-volumic equivalent maltose-dextrin milk solution served as controls. The in vitro model consisted of cerebral cortical neuron cultures from embryonic day (ED) 16⁻17 fetus from SD rats and differentiated neurons from ED18 rat cerebral cortical neuroblasts. E concentrations were 4 mg/mL. E induced an accumulation of cystathionine in primary cortical neurons (PCNs), 2nd trimester equivalent in utero binge, and 3rd trimester equivalent PN7 model suggesting that breakdown of cystathionine, a required process for Cys supply is impaired. This was associated with a significant reduction in cystathionine γ-lyase (CSE) protein expression in PCN (p < 0.05) and in fetal cerebral cortex in utero (53%, p < 0.05) without a change in the expression of cystathionine ß-synthase (CBS). Concomitantly, E decreased Cse mRNA expression in PCNs (by 32% within 6 h of exposure, p < 0.05) and in fetal brain (33%, p < 0.05). In parallel, knock down of CSE in differentiated rat cortical neuroblasts exaggerated the E-induced ROS, GSH loss with a pronounced caspase-3 activation and cell death. These studies illustrate the importance of TSP in CSE-related maintenance of GSH and the downstream events via Cys synthesis in neurons and fetal brain.

Prenatal Hypoxia Ischemia Increases Male Rat Sexual Behavior.

INTRODUCTION: Research consistently indicates an association between prenatal hypoxia-ischemia (HI) and mortality and chronic neurological diseases in newborns. HI can cause permanent effects, including mental retardation, motor impairment, learning disabilities, epilepsy, and cerebral palsy. Moreover, little is known about the relationship between HI and sexual behavior. AIMS: The aims of this study are to examine whether HI is associated with changes in sexual behavior. METHODS: HI was induced by clamping the uterine arteries of pregnant rats. The arteries were clamped for 45 minutes on the 18th day of gestation (HI group). Shams received laparotomy and anesthesia only. Pups were born at term. At 90 days of age, sexual behavior was evaluated. Statistical analysis was performed using two-way analysis of variance and post hoc Bonferonni correction. MAIN OUTCOME MEASURES: The main outcome measures of sexual response were standard sexual behavior, homosexual behavior, and sexual attempt on nonreceptive females. RESULTS: The stimulatory effect of HI on male rat sexual behavior has been shown in various experimental models; these animals showed reduced mount, intromission and ejaculation latencies; increased copulatory efficiency; and homosexual mounting. Additionally, there was an increase in fighting in trying to mount an unreceptive female. CONCLUSION: Our results indicate that HI had a long-term effect on sexual behavior despite exhibiting motor skill impairment. Accordingly, injuries during the fetal period may cause behavioral problems in adulthood.

Intrauterine fetal decapitation after a high-speed car crash.

Motor vehicle collisions are an important cause of blunt abdominal trauma in pregnant woman. Among the possible outcomes of blunt abdominal trauma, placental abruption, direct fetal trauma, and rupture of the gravid uterus are described. An interesting case of complete fetal decapitation with uterine rupture due to a high-velocity motor vehicle collision is described. The external examination of the fetus showed a disconnection between the cervical vertebrae C3 and C4. The autopsy examination showed hematic infiltration of the epicranic soft tissues, an overlap of the parietal bones, and a subarachnoid hemorrhage in the posterior part of interparietal area. Histological analysis was carried out showing a lack of epithelium and hemorrhages in the subcutaneous tissue, a hematic infiltration between the muscular fibers of the neck and between the collagen and deep muscular fibers of the tracheal wall. Specimens collected from the placenta and from the uterus showed a hematic infiltration with hypotrophy of the placental villi, fibrosis of the mesenchymal villi with ischemic phenomena of the membrane. The convergence of circumstantial data, autopsy results, and histological data led us to conclude that the neck lesion was vital and the cause of death was attributed to the motor vehicle collision.

Fetal laceration during caesarean section and its medico-legal sequelae.

Fetal laceration is a recognized complication of caesarean delivery. The aim of this study was to investigate the incidence, type, location, risk factors and long-term consequences of accidental fetal incised wounds during caesarean delivery. During a five-year period, we observed 25 cases of fetal lacerations caused by the scalpel during hysterotomy. In 20 of these cases, we observed these lesions as consultants for the Neonatologic Care Unit; the other five cases came under our care after an insurance claim for damages against the gynaecologist. All the infants had a lesion located to the head. In only 5 of the 25 cases the lesion was reported in the operative summary, and only 16 of the 25 mothers had signed an informed consent before surgery. With regard to the 20 cases diagnosed at the Neonatologic Care Unit, the lesion was closed using single stitches in nine cases, and with biological glue in 11 cases. Concerning the five cases that underwent legal proceedings against the gynaecologist, a clinical examination was performed by an expert in Public Health and Social Security in collaboration with a paediatric surgeon to evaluate the degree of biological damage. In all five cases, the result of the legal challenge was monetary compensation for the physical and moral damage caused by the gynaecologists to the patients and their parents. Accidental fetal lesions may occur during caesarean delivery; the incidence is significantly higher during emergency caesarean delivery compared to elective procedures. Patients should sign an informed consent in which they should be informed about the risk of the occurrence of fetal lacerations during caesarean delivery in order to avoid legal complications.

Role of oxidative injury in affecting the foetal & placental weights on exposure to tobacco smoke.

OBJECTIVE: To investigate the role of oxidative injury in affecting foetal and placental weights in mice by exposing them to tobacco smoke with or without supplementation with antioxidants. METHODS: The randomized control trial of pregnant mice at day one of gestation was conducted at Anatomy Department CPSP Regional Center Islamabad, from March 2005 to October 2005. The mice were divided into three groups: Group C had controls, while the two other groups, groups S and SV were exposed to secondary tobacco smoke in a whole body exposure chamber with and without supplementation with vitamins respectively. At term, the animals were sacrificed and the placentae and foetuses were weighed. The average values were calculated. The means for each group were analysed and the foetal placental ratio was calculated. SPSS 17 was used for statistical analysis. RESULTS: There were 44 mice; 15(34%) each in S and SV groups, while Group C had 14(32%) mice who acted as the controls. The mean foetal weight in Group S was 0.65±0.52g which was significantly less (p<0.0001) than1.48±0.19g in Group C. The mean foetal weight in Group SV was 0.97±0.65g which was not significantly different from S (p=0.124). The mean placental weight in Group S was 0.16±0.02g which was significantly less than 0.21±0.05gin Group C (p=0.014). In Group SV it was significantly more than Group S (p<0.0001). The ratio of mean foetal and mean placental weights in the groups C, S and SV were 7.05, 3.92 and4.41 respectively. CONCLUSIONS: Prenatal exposure to tobacco smoke decreased the mean foetal and placental weights and the foetal-placental ratio. This may partly be attributed to oxidative injury induced by free radicals in the tobacco smoke as it is prevented to some extent by simultaneous administration of antioxidants.

Fetal intracranial injuries following motor vehicle accidents with airbag deployment.

The effects of airbag deployment in motor vehicle accidents (MVA) on the fetus are poorly understood. A 22-year-old woman at 24 weeks of gestation collided with a telephone pole while driving. She was restrained and an airbag deployed. Although she had no major injuries, she experienced decreased fetal movements. Fetal heart rate (FHR) monitoring revealed loss of variability without any evidence of abruptio placentae, and 4 days later, the variability spontaneously recovered. Two weeks after the MVA, ultrasonography showed unilateral ventricular dilatation suggestive of fetal brain injury. Magnetic resonance imaging revealed subdural hematoma, intraventricular hemorrhage and cystic lesions, interpreted as indirect (hypoxic-ischemic) and direct (hemorrhagic) intracranial injuries. After MVA with airbag deployment, FHR monitoring can show a transient loss of variability, which may precede the appearance of fetal brain injury.

Pathophysiological mechanisms of impaired limb use and repair strategies for motor systems after unilateral injury of the developing brain.

The corticospinal tract (CST) is important for limb control. In humans, it begins developing prenatally but CST connections do not have a mature pattern until about 6 months of age and its capacity to evoke muscle contraction does not mature until mid-adolescence. An initially bilateral projection is subsequently refined, so that most ipsilateral CST connections are eliminated. Unilateral brain damage during refinement leads to bilateral developmental impairments. The damaged side develops sparse and weak contralateral spinal connections and the non-involved hemisphere maintains its ipsilateral projection to develop an aberrant bilateral spinal projection. In a kitten model of unilateral spastic cerebral palsy, we replicate key features of the CST circuit changes: robust bilateral CST projections from the non-involved hemisphere, sparse contralateral connections from the affected hemisphere, and motor impairments. We discuss the role of activity-dependent synaptic competition in development of bilateral CSTs and consider several experimental strategies for restoring a more normal pattern of CST connections from the damaged and non-involved sides. We highlight recent results stressing the importance of combined repair of CST axons, restoration of a more normal motor cortex motor representation, and key involvement of spinal cholinergic interneurons in restoring skilled motor function.

Cutaneous foetal injuries related to amniocentesis.

Amniocentesis is one of the most important prenatal diagnostic procedures available to assess congenital abnormalities. It is performed worldwide due to its simplicity of execution and lack of risk. The most frequent known accidents in amniocentesis are abortion, oligohydramnios, amniositis and placental abruption, while direct fetal injuries produced by contact with the needle are rarely seen. The injuries produced are extremely variable in severity, but the most frequent is skin wounds, which usually heal as small, round depressed scars. The cases we describe concern the occurrence of iatrogenic cutaneous wound lesions to a fetus during amniocentesis. The medical-legal analysis of the cases required dermatological expertise in order to exclude a different pathogenesis for the skin injuries to the child and were assigned by the court, in order to assess the administrative compensation due to the parents of the child as a result of medical malpractice.

[Residual pellet in fetal brain tissue following a gunshot injury to a pregnant woman: a case report]. / Gebe bir kadinda av tüfegi yaralanmasi sonucu fetüs beyin dokusunda rezidüel saçma tanesi: Bir olgu sunumu.

Vital functions and the effect of injuries on quality of life are important from a viewpoint of causation in willful injury crimes committed against a pregnant woman. In such conditions, which should be evaluated separately in criminal law and compensation law, permanent losses of organ function that may negatively affect the woman's fertility, the features of permanent functional impairments and premature birth of the fetus can be additive factors for the indemnification amount. In scientific literature, case reports addressing the morphological and physiological changes to the fetus due to firearm injury are rare. In the presented case, we aimed to evaluate the fetus's situation, following firearm injury to a 41-year-old woman at 27 weeks gestation. While the mother was living a healthy life, the significant problem of the child in the first four-year period of his development was hyperactivity. Evaluating the effect of the frontal lobe lesion on the psychiatric findings of the child is important.

Liability and maternal immunization: in utero injury claims in the VICP.

Generally, under the National Childhood Vaccine Injury Act of 1986 (Vaccine Act), vaccine administrators and manufacturers are shielded from medical malpractice or products liability actions stemming from vaccine-related injuries and deaths. That said, as generous as these protections may be, they have boundaries, some of which are clear and others of which are unsettled. This is particularly so for in utero injuries stemming from immunization of pregnant women. The issue of whether in utero injuries are afforded such protections, vis á vis compensation by the National Vaccine Injury Compensation Program (VICP) under the Vaccine Act, has not definitively been resolved by the courts. Short of a decision by the Court of Appeals for the Federal Circuit or a statutory amendment by Congress specifically addressing this issue, the uncertainty remains.

[Cell phones: health risks and prevention]. / Telefoni cellulari: rischi per la salute e strategie di prevenzione.

The paper describes first of all the electromagnetic radiation of cellular phones and presents the physical parameters used to measure and evaluate the absorption of emissions of radio stations and cellular phones. It then presents selected research results of the experimental studies in vivo and in vitro which examine the biological effects of the emissions of cellular phones. The review of the epidemiologic evidence focuses in particular the epidemiologic studies on the use of cell phones and brain tumours, identifying some of the reasons of the conflicting results obtained. Studies dealing with the health risks involved in the increasing use of cellular phones by adolescents and children, more sensitive to this exposure, are also presented showing the need for special caution. The problem of hypersensitivity observed in some individuals is also briefly discussed. Finally the paper presents a summary of the main prevention measures necessary in order to reduce the risks in the framework of the "precautionary principle" including prevention policies and exposure limits in various countries.

Obstetric and neonatal outcomes of cancer treated during pregnancy.

Cancer diagnosed during pregnancy is a rare occurrence with an incidence of 0.1% of all pregnancies. However, its management can be challenging at times as one balances maternal benefit to fetal risk. Various treatment modalities are used in this context including surgical intervention, chemotherapy, and radiologic therapy. This review seeks to address the impact of pregnancy on disease as well as the effect of malignancy and its treatment on both mother and fetus. Attention is focused on the more common malignancies associated with pregnancy: cervix, breast, melanoma, and hematologic malignancies. In addition, special emphasis is placed on timing of delivery and how that affects neonatal outcomes.

Cancer in pregnancy: fetal and neonatal outcomes.

Cancer during pregnancy represents a potential conflict between optimal maternal treatment and fetal development. Traditionally, clinicians operated under the assumption that cancer treatment during pregnancy is incompatible with normal fetal development. However, recent evidence suggests that many diagnostic and treatment modalities cause little or no harm to the developing fetus. As such, both maternal and neonatal interests should be considered when developing management strategies for pregnant cancer patients. In this review, we will discuss issues related to fetal and neonatal health associated with conventional diagnostic and treatment approaches in the care of pregnant women with cancer. In addition, we offer recommendations on strategies to maximize fetal outcomes in pregnancies complicated by cancer.

[Pregnancy and trauma].

Anatomic and physiologic changes in pregnancy can mask or mimic injury, making diagnosis of trauma-related problems difficult. Care of pregnant trauma patients with severe injuries often requires a multidisciplinary approach involving an emergency clinician, trauma surgeon, obstetrician, anesthesiologist and neonatologist. The pregnant trauma patient presents a unique challenge because care must be provided for two patients--the mother and the fetus.